WO2018190621A1 - Préparation à libération prolongée comprenant une couche de rétention gastrique poreuse, et son procédé de préparation - Google Patents

Préparation à libération prolongée comprenant une couche de rétention gastrique poreuse, et son procédé de préparation Download PDF

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WO2018190621A1
WO2018190621A1 PCT/KR2018/004209 KR2018004209W WO2018190621A1 WO 2018190621 A1 WO2018190621 A1 WO 2018190621A1 KR 2018004209 W KR2018004209 W KR 2018004209W WO 2018190621 A1 WO2018190621 A1 WO 2018190621A1
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layer
drug
sustained release
sustained
formulation
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PCT/KR2018/004209
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Korean (ko)
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박은석
김주영
김수현
황규목
조철희
트람 응왼티
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성균관대학교 산학협력단
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Priority claimed from KR1020180040904A external-priority patent/KR102046248B1/ko
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Publication of WO2018190621A1 publication Critical patent/WO2018190621A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to a sustained release formulation comprising a gastric retention layer and a preparation method thereof.
  • a gastroenterological drug delivery system is a drug delivery system in which a drug is continuously released in the gastrointestinal tract, and is mainly used to increase the bioavailability of a drug having a limited absorption site.
  • the swelling type system is not easy to control the rate of drug release, the strength of the formulation itself is weakened as the formulation swells, the gastrointestinal movement in the body can not be sustained, the system collapsed early and showed a limit to pass through the pylorus.
  • Korean Registered Patent Nos. 1226215, 11269829, 1270751, 1271702 and 1313192 use a swellable polymer and a bubble generator together to lower the density of the preparation in the gastric environment. Has been disclosed.
  • This floating system has the advantage of significantly increasing gastric retention time by increasing the physical distance from the pylorus, but there is a delay before bubbles can be generated and it can pass through the pylorus before it floats and the patient is Depending on the lying position, there is a limit that the drug release time in the gastrointestinal tract can be shortened through the pylorus.
  • the non-swellable polymer and the foaming agent that can maintain the strength in the wet state at the same time when the formulation is likely to disintegrate on the principle similar to the foamed tablets, only the swellable polymer can be used.
  • the swellable polymer is used to enhance the strength, there is a disadvantage in that the suspension delay time occurs due to the diffusion inhibitory effect of the water into the formulation.
  • a sublimation material is sublimed by vacuum drying or hot air drying using a sublimable material in the manufacturing process to form pores to maintain the porous form in the tablet in advance, so that the density is low before taking.
  • floating gastric drug delivery system and a method of manufacturing the same have been proposed, floating gastric body retention system using such a porous structure does not sufficiently secure the strength of the formulation when applied in vivo (in vivo). There was a big deviation in the results of collapse and gastric retention, and drug release also showed a big deviation.
  • the molecular weight of the swellable polymer and the ratio in the formulation increase the gastric flow.
  • the drug pharmaceutically active substance
  • the inventors of the present invention by forming a plurality of pores in the gastric retention layer by using a sublimable material, by preparing a bilayer tablet formulation separating the gastric retention layer and the drug release layer, it has a high strength to withstand the movement of the gastrointestinal tract and can be suspended immediately. It was confirmed that the formulation can be prepared and the present invention was completed based on this.
  • It is an object of the present invention to provide a sustained release formulation comprising a drug release layer and a porous gastroretentive layer.
  • Another object of the present invention is to provide a method for preparing the sustained release formulation.
  • the present invention comprises the steps of mixing the drug and the sustained release agent (S1); Preparing a drug release layer mixture by mixing a binder, excipient or glidant with the mixed drug and sustained-release agent (S2); Preparing a gastric retention layer mixture by mixing a swellable polymer or a non-swellable polymer with a sublimable material and a lubricant (S3); Preparing a two-layered tablet including a drug release layer and a gastric retention layer by multi-layer tableting of the mixture of the step S2 and the mixture of step S3 (S4); And subliming the sublimable material in the bilayer tablet to form pores (S5).
  • the sublimable material may be one or more selected from the group consisting of camphor, menthol, urea and mixtures thereof.
  • the sublimable material in step S3 may be mixed 5 to 25% by weight based on the total weight of the sustained release formulation.
  • the present invention provides a sustained release formulation prepared by the above method.
  • the present invention also provides a sustained-release preparation of a two-layered tablet comprising a drug release layer and a gastric retention layer, wherein the drug release layer comprises a drug and a sustained release agent, and the gastric retention layer has a porous structure to provide a swellable polymer or a non-swellable polymer. It provides a sustained release formulation comprising.
  • the sustained release formulation may be characterized in that it does not contain a bubble generator.
  • the sustained release formulation may have a density of 0.5 g / mL to 1 g / mL due to the porous gastric retention layer, and may be immediately suspended in a milky sap, an eluate, and a digestive fluid.
  • the sustained release formulation may have a suspended retention time of 10 to 36 hours by a second dissolution test method (paddle method) under a pH 1.2 eluate condition.
  • the drug release layer may be included in 10 to 90% by weight based on the total weight of the sustained release formulation.
  • Porous gastric sustained release formulation of the bilayer structure according to the present invention is separated from the drug release layer and the porous gastric retention layer to easily control the release of the drug, has the advantage of excellent bioavailability, including the existing bubble generator Unlike the gastric retention system, it is possible to lower the density of the formulation in advance during the manufacturing process, so that it is suspended in the food and digestive fluid in the stomach immediately after taking it, thereby fundamentally blocking the possibility of initial passage through a physical distance from the pylorus.
  • the density can be freely adjusted according to the amount of the sublimable substance so that the dosage form can be immediately suspended regardless of the weight of the drug release layer.
  • the volume of the formulation may be made into round / rectangular tablets of 11 mm or more, minimizing the passage of the pylorus in the patient's lying down situation.
  • the formulation contains a large amount of swellable and non-swellable polymers to overcome the above factors and includes a large amount of polymer
  • the retention layer is structurally separated from the drug release layer. Therefore, the excessive dissolution rate reduction phenomenon generally occurring in single-layered crystals while containing a large amount of these can be avoided. Since the phenomena can be avoided, the ratio of the swellable and non-swellable polymer of the gastric retention layer can be set to concentrate on the gastric retention effect, and the polymer ratio of the drug release layer can be set to concentrate on the dissolution of the formulation. Therefore, in the case of the formulation, the dissolution rate may be set to a sustained release formulation in which release is completed in 2 to 24 hours.
  • the formulation when the bubble is formed in the eluate, the formulation is more likely to lose its initial form on the same principle as the expanded tablet disintegrates, but in the case of the bilayer porous gastrointestinal preparation according to the present invention Because pores are formed through the process, disintegration of the formulation does not occur.
  • a non-swellable polymer it is possible to further increase the wet strength, that is, the gastric retention capacity of the formulation to withstand gastric contraction movement.
  • the formulation has the advantage that it is not viscous to eliminate the risk of gastrointestinal obstruction.
  • the sustained-release preparation is immediately suspended when ingested by the floating force that pores are formed in the porous gastric fluid layer so that the porous gastric fluid layer can be always located in the upper part of the stomach, so that the drug-releasing layer is the upper part of the body fluid It is not exposed to have a feature that can maintain the drug release for a long time, thereby enabling to specifically stay in the absorption site for a long time has the effect of maximizing the drug efficacy.
  • FIG. 2 is a diagram schematically illustrating a method for preparing a formulation of the present invention.
  • Figure 3 is a graph showing the density change before and after sublimation according to the type and weight ratio of the sublimable material of the gastric retention layer prepared in the embodiment of the present invention.
  • Figure 4 is a result of confirming the sublimation rate of the sublimable material for each time zone by varying the content of the sublimable material and the type of the swellable polymer.
  • Figure 5 is a view showing the result confirmed by the scanning electron microscope of the porous gastric retention layer of the preparation prepared in the embodiment of the present invention.
  • FIG. 6 is a view showing the results of confirming the tablet wet strength of the formulation prepared in the embodiment of the present invention.
  • Figure 13 shows the results of confirming the gastric retention time of the porous bilayer preparation (A) and the monolayer control preparation (B) prepared in the embodiment of the present invention in the experimental animal.
  • the present invention has been made to develop a gastric retention system with excellent bioavailability and strength.
  • a sustained-release oral dosage form in a tablet form consisting of a bilayer of a drug release layer containing a pharmacologically active ingredient and a porous gastric retention layer excluding the active ingredient is provided. It was confirmed that there is an excellent bioavailability and excellent tablet strength, the present invention was completed.
  • the present invention is a sustained release formulation comprising a drug release layer and a porous gastric retention layer, wherein the drug release layer comprises a drug and a sustained release agent, and the porous gastric retention layer includes a swellable polymer or a non-swellable polymer. It provides a sustained release formulation in which pores are formed through a chemical material.
  • the present invention also provides a method for preparing a sustained release formulation comprising the following steps:
  • Preparing a drug release layer mixture by mixing a binder, excipient or glidant with the mixed drug and sustained-release agent (S2);
  • Preparing a gastric retention layer mixture by mixing a swellable polymer or a non-swellable polymer with a sublimable material (S3);
  • Sustained release formulation of the present invention is characterized in that by forming a pore in advance through the sublimation process to ensure a floating effect without including a bubble generator such as sodium carbonate in the formulation.
  • the formulation according to the present invention has a density of 1 g / mL or less and is 0.5 g / mL to 1 g / mL.
  • swellable / non-swellable polymers belonging to the porous gastric retention layer which provide strength to the formulation to withstand peristalsis / segmental movement of the gastrointestinal tract while maintaining low-density suspension effects due to low density, are drug release Since only the layer contains the pharmacologically active ingredient, the porous gastric retention layer and the drug release layer are separated from each other, and are not mixed, the gastric retention layer affects the release of the pharmacologically active component of the drug release layer. It does not affect, and the drug release layer has an effect that does not affect the floating effect of the gastroretentive layer. In other words, there is an advantage that you do not have to lose any of the gastric resident ability and drug release.
  • the formulation of the present invention is circular or rectangular, characterized in that the length of the long side is 11mm to 22mm, by ensuring a sufficient volume along the length of the above range, the phenomenon of passing through the pylorus of the patient taken You can prevent it.
  • Sustained-release preparation prepared by the above method is that the pores are formed in the gastric retention layer, so that the floating force is generated, so that the ingestion of the preparation immediately floats in the stomach so that the gastric retention layer is always in the stomach of the body fluids Upper side), which causes the drug release layer to be positioned below the surface of the water, so that the drug release layer is not exposed to the surface of the water (the upper part of the body fluid) so that the drug release can be kept constant for a long time.
  • the gastric retention layer may include a swellable polymer or a non-swellable polymer.
  • the swellable polymer may have a swelling prevention function through rapid swelling and adhesiveness, and when the non-swellable polymer is included, damage to the preparation due to peristaltic / segmental movement may be reduced, and repeated administration It is possible to prevent side effects such as intestinal obstruction by, and can be selected and prepared according to the treatment method, period, or purpose of the preparation to be produced.
  • the drug release layer may be included in 10 to 90% by weight relative to the total weight of the sustained release formulation. If the ratio of the drug release layer is very low, less than 10% by weight, it is difficult to secure the uniformity of the content using a double-layer tablet press during actual production, and when the ratio of the drug release layer is very high, exceeding 90% by weight, the overall formulation As a result, the porosity of the gastric retention layer may be increased in order to obtain a low density, and thus the wear and tear may be increased, and the hardness may be lowered, and thus it may not be able to endure subsequent processes such as a coating process.
  • the drug (pharmacologically active ingredient) may be included as long as it is a drug that requires drug delivery by the sustained-release system, the drug is directly in the upper portion of the small intestine, gastric ulcers, such as a drug for the local treatment of the formulation directly It may be a drug to be stayed.
  • the drug of the present invention is levamipid, leaf extract, ranitidine, pregabalin, gabapentin, metformin, limaprost, ciprofloxacin, levodopa, trazodone, levamipid, fenofibric acid, etopriide, mosaprid, terpenone , Simvastatin, atorvastatin, pravastatin, pitavastatin, balsa, rozatan, candesartan, olmesartan, azisartan, amoxicillin, azithromycin, carbamazepine, paracetamol, diclofenac, metoclopramide, pioglitazone, Allopyridol, valsartan, candesartan, eprosartan, ibesartan, telmisartan, furosemide, nifedipine, verapamil, pamotidine, itraconazole, cyclo
  • the drug release layer may further include a binder, an excipient or a lubricant.
  • the binder may be povidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, gelatin, guar gum, xanthan gum, and the like, which are mixed with the pharmacologically active ingredient in a dry powder state or dissolved in the binder solution.
  • the drug and the binder or excipient may be granulated and mixed.
  • the granulation process is a process for enhancing the fluidity and tableting of the mixture of the drug and the binder or excipient
  • the type of the process is not particularly limited, for example, granulation may be performed by a dry method, a wet method or a fluidized bed granulation method. have.
  • the manufacturing process using a double binder solution is a wet method, a fluidized bed granulation method, and the manufacturing process using a binder without a binder solution is a dry method.
  • the excipient is good tabletting, can be used without limitation depending on the type of drug or the state of the granules, preferably lactose, microcrystalline cellulose, dibasic calcium phosphate, etc. may be used, but It is not.
  • the lubricant may be used to adjust the flowability of the granules, preferably colloidal silicon dioxide, magnesium stearate, or talc may be used, but is not limited thereto.
  • the sustained-release agent may be mixed before or after granulation of the drug, the sustained-release agent may be methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, alginic acid Sodium, polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, guar gum, acrylic acid copolymer, carbomer, ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinylacetate / polyvinylpyrrolidone, zein, Shellac, methacrylic acid copolymer, beeswax, carnauba wax, paraffin wax, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, plant hardened oil, cottonse hardened oil, castor hardened oil, Soy bean cured
  • the sublimable material for forming the porosity may include a camphor, menthol, or urea.
  • the particle size control of the sublimable material is secured through a grinding process, and the type is not particularly limited as long as it is a process capable of obtaining an appropriate particle size of the sublimable material.
  • the sublimable material may be adjusted to particle size using a hammer mill, conical mill, or the like, and may adjust screen size, screen shape, impeller type, and the like. For example, when the sublimable material is administered to the hammer mill at a constant rate, a sublimable material having an appropriate particle size can be obtained in a subsequent process, and the screen size is screen blinding during the grinding process. ) 100 ⁇ 1500 ⁇ m can be selected on the line where no effect occurs, and the screen shape can be manufactured using round or grater.
  • the sublimable material of the present invention may be one having a particle size of 600 to 1000 ⁇ m or more diameter of at least 50% of the powder obtained through the sieve analysis, if necessary further proceeds to the secondary grinding process or apple process to more appropriate distribution Can have
  • the sublimable material of the present invention is preferably mixed 5 to 25% by weight relative to the total weight of the sustained release formulation. If the sublimable material is treated at less than 5% by weight, it may be difficult to secure sufficient density to float because the pores are not sufficiently formed in the gastric retention layer. If the sublimable material is processed at more than 25% by weight, the purification after the sublimation process is performed. May crack or the hardness may become low.
  • a lubricant may be added before or after mixing with the polymer to ensure proper fluidity and prevent aggregation of the sublimable material during mixing of the sublimable material with the swellable or non-swellable polymer.
  • the swellable and non-swellable polymers used in the above process are not particularly limited as long as they are components that can increase the resistance to gastrointestinal motility of the final tablet.
  • swellable polymers methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose , Hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, guar gum, acrylic acid copolymer, carbomer or mixtures thereof and the like.
  • non-swellable polymers ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinylacetate / polyvinylpyrrolidone, zein, shellac, methacrylic acid copolymer, beeswax, carnauba wax, paraffin wax, cetyl alcohol, cetoste Aryl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, plant hardened oil, cottonse hardened oil, castor hardened oil, soy hardened oil, mixtures thereof, and the like.
  • the preparation of the two-layered tablet may be tableted using a two-layered tablet press and the tableting pressure, the order of tableting of the gastroretentive layer / drug release layer is changed according to the type of active ingredient and the composition of the drug release layer Can be.
  • step S5 of the present invention in the sublimation step of the sublimable material, it is possible to remove the sublimable material from the formulation by vaporization / sublimation through warm drying to form pores, thereby completely subliming the sublimable material. It may not include pore-forming material.
  • Heating drying required for the removal of the sublimable material may be hot air drying and vacuum drying, but is not limited thereto.
  • the drying temperature may be maintained at a temperature of 20 °C to 80 °C depending on the stability of the drug, in the case of drying time proceeds by checking the time that the sublimable material can be completely removed in the formulation.
  • Tablets prepared according to the manufacturing method of the present invention do not need to apply a low compression pressure to secure a low density according to the characteristics that the pores are formed after the tableting has the ability to be suspended immediately before the hardness and hardness required for transportation and coating process It has the advantage of having.
  • the non-swellable polymer has a strength in terms of enduring intense gastrointestinal peristalsis, and the swellable polymer has a strength in terms of not passing through the pylorus (see Experimental Example 5-2).
  • swellable polymers it was confirmed that proper blending of pores and polymers was required in terms of strength against compression and hardness of the tablet itself (see Experimental Example 5-3), and it could resist further processing of tablets and gastrointestinal peristalsis. It was confirmed that control of the type and content of the sublimable material is necessary to retain hardness and strength (see Experimental Example 5-4).
  • the preparation according to the method of the present invention may be immediately suspended by forming a plurality of pores through the sublimation process in the manufacturing process to maintain low density, and the strength of the porous gastric retention layer is different from the conventional gastric retention system for a long time. Maintaining rigidity, there is an advantage that the drug release can be made freely because the gastric retention layer and the drug release layer is separated.
  • the porous gastric retention layer was completed by mixing camphor or menthol, and swellable polymer polyethylene oxide (7M) and hydroxypropylmethylcellulose. Then, using a hydraulic tableting machine was compressed into 10 mm round tablets.
  • camphor or menthol was mixed at 5, 10, 15, 20, 25% w / w with respect to the total mass of the gastric retention layer 500 mg, and the hardness of Experiment 5-5 was adjusted.
  • the camphor or menthol was mixed at 10, 20, 30, 40% w / w for a total mass of 500 mg of gastric retention layer.
  • a porous gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours to sublimate the sublimable material of the gastric retention layer.
  • camphor or menthol was mixed with 30 and 40% w / w of 600 mg of the total mass of the gastric retention layer and compressed into 16 mm rectangular tablets. After tableting at a pressure of 60 °C, the weight was checked at a predetermined time by vacuum drying at 60 ° C. to determine how much the weight of the initial sublimable substance was sublimated (weight was reduced).
  • levamipid 150 mg of levamipid, 150 mg of microcrystalline cellulose (Avicel PH 101), and 20 mg of croscarmellose sodium were dissolved in 5% polyvinylpyrrolidone (povidone) K30 in 70% ethanol aqueous solution.
  • povidone polyvinylpyrrolidone K30 in 70% ethanol aqueous solution.
  • the prepared granules were cross-linked with hydroxyethyl cellulose (Example 2-1), polyethylene oxide (Example 2-2), or hydroxypropylmethyl cellulose (Example 2-3), microcrystalline cellulose (Vivapur 12), and cross.
  • the drug release layer mixture was completed by mixing with sodium carmellose, red No. 2 aluminum lake, colloidal silicon dioxide, and magnesium stearate.
  • Gastric retention layer was completed by mixing the camphor, polyethylene oxide (7M), colloidal silicon dioxide, magnesium stearate. After that, using a hydraulic tableting machine was compressed into a 16 mm rectangular tablet. The content of each component in the obtained uncoated tablet is shown in Table 1 below. Then, a porous bilayer tablet was prepared in which a plurality of pores were formed in the gastric retention layer by proceeding for at least 12 hours under vacuum drying at 60 ° C. to sublimate the sublimable material of the gastric retention layer (campus removal).
  • Granules were prepared using a binding solution of 150 mg of levamipid, 150 mg of microcrystalline cellulose, and 20 mg of croscarmellose sodium as a pharmacologically active ingredient, in which 5% polyvinylpyrrolidone (povidone) K30 was dissolved in 70% ethanol aqueous solution. After apology to No. 45 body.
  • the prepared granules were hydroxyethyl cellulose (Example 3-1), polyethylene oxide (Example 3-2), or hydroxypropylmethyl cellulose (Example 3-3), microcrystalline cellulose and croscarmellose sodium cross.
  • Sodium cameloose, red No. 2 aluminum lake, colloidal silicon dioxide, and magnesium stearate were mixed to complete the drug release layer mixture.
  • the gastric retention layer was completed by mixing a camphor, a mixture of polyvinylacetate and povidone, colloidal silicon dioxide, and magnesium stearate. After that, using a hydraulic tableting machine was compressed into a 16 mm rectangular tablet. The content of each component in the obtained uncoated tablet is shown in Table 2 below.
  • a porous bilayer tablet having a plurality of pores formed in the gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
  • Levamifeed sustained-release preparations were prepared in the same manner as in Examples 2 and 3, except that the tablets were compressed into 8 mm round tablets and did not include a gastric retention layer.
  • a gastric, sustained-release tablet containing foaming substances was used as a 10-mm round tablet, and commercially available Eufacidin® R tablets containing natural extracts, bile isopropanol, and crude extracts were used as active ingredients.
  • a binding solution containing 300 mg of levamipid, 300 mg of microcrystalline cellulose (Avicel PH 101), and 5% w / v polyvinylpyrrolidone (povidone) K30 in 70% v / v ethanol aqueous solution was used.
  • the granules were prepared and appled in a No. 45 sieve.
  • the granules thus prepared were mixed with polyethylene oxide 1 M, microcrystalline cellulose (Vivapur 12), camphor, and magnesium stearate to complete a single layer. Thereafter, the tablets were compressed into 19 mm rectangular tablets using a Natoli tablet press.
  • the content of each component in the obtained uncoated tablet is shown in Table 3 below.
  • a porous monolayer tablet was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
  • the sublimation rate of the sublimable material was confirmed at different times by varying the content of the sublimable polymer and the type of the swellable polymer.
  • the weight of the tablet no longer decreases after the tablet has been reduced by the amount of camphor (after 3 hours). Mensol was also slower than the camper but removed 24 hours later.
  • the sublimation process was homogeneously completed regardless of the type of polymer such as hydroxypropyl methyl cellulose (HPMC), polyethylene oxide (PEO).
  • the pores are not formed because the camper does not sublimate when not subjected to the sublimation process, it can be confirmed that the pores are formed evenly formed through the sublimation process. Therefore, it was confirmed that the preparation according to the present invention can be expected to be immediately suspended and improved gastric retention effect by using a low-density property immediately after preparation. In addition, it was confirmed that a large number of pores were formed through the sublimation process even in the case of using a non-swellable polymer that was limited in the existing bubble generation system.
  • a dissolution test second method (paddle method, 100 rpm, 37 ° C.) was performed in a pH 1.2 solution.
  • Hardness and wear and tear evaluation of the bilayer sustained release tablet and the monolayer sustained release tablet using the porous gastric retention system of the present invention was carried out. Hardness evaluation of tablets was confirmed using a hardness tester (Tablet Tester 6D, Dr. Schleuniger, Thun, Switzerland). The friability was taken as much as 6.5 g and the weight change was measured before and after after 100 revolutions for 4 minutes at 25 rpm in a friability meter (FAT-10, Fine Scientific Instrument, Anyang, Korea). Table 5 shows the results of hardness and wear and tear.
  • Example 3-3 has a higher hardness and lower wear value than Comparative Example 3. Both formulations were negatively affected by hardness and wear and tear through the sublimation process, but it can be seen that the bilayer sustained-release tablet using the porous gastric retention system according to the present invention has better tablet characteristics than the monolayer sustained-release tablet.
  • the strength of the tablet was evaluated after exposing it for a certain time in the eluate.
  • Example 3-3 has a much higher tablet strength even after a long time exposure in dissolution conditions than Comparative Example 3. This can be inferred from Example 3-3 that the strength that can stand in the stomach even after taking the actual tablets, confirming that the gastric retention effect can be long lasting.
  • a tablet made with a representative swellable polymer polyethylene oxide (molecular weight 7,000,000), PEO 7M) or a representative non-swellable polymer (a mixture of polyvinylacetate and povidone, Kollidon SR) can stand in the stomach environment After exposure for a certain time in the eluator, the strength of the tablets was evaluated.
  • a representative swellable polymer polyethylene oxide (molecular weight 7,000,000), PEO 7M) or a representative non-swellable polymer (a mixture of polyvinylacetate and povidone, Kollidon SR)
  • polyethylene oxide which is a representative swellable polymer
  • the mixture of vinyl acetate and povidone (Kollidon SR) is high. Therefore, non-swellable polymers have strengths in the characteristics of gastric retention formulations that must withstand intense gastrointestinal peristalsis, and swellable polymers have strengths in the size of the formulations in the characteristics of gastric retention formulations that should not pass through the pylorus.
  • the strength of the tablet was evaluated after exposing for a predetermined time. At this time, the strength of the drug release layer itself was compared to the strength after preparing the gastric retention layer only in order not to affect the strength comparison experiment of the gastric retention layer.
  • the porous gastric retention layer was completed by mixing 20% by weight of camphor and a typical swellable polymer such as polyethylene oxide, hydroxyethyl cellulose, and hydroxypropyl methyl cellulose.
  • the nonporous common gastric layer did not mix the camphor.
  • the total mass of the gastric retention layer is 450 mg, mixed with camphor 0 or 20% w / w, and magnesium stearate at 0.5% w / w, and tableted at a pressure of 1 ton using a 10 mm round-flat hydraulic tablet press.
  • a porous or non-porous general gastric retention layer was prepared by proceeding with vacuum drying at 60 ° C. for at least 12 hours.
  • the prepared porous or non-porous common gastric fluid layer was exposed to 900 mL of pH 1.2 eluate at 50 rpm and 37 ° C. for 0, 2, 6, and 12 hours, and then purified.
  • the diameter of the tablet was measured using a texture analyzer. .
  • the measurement conditions were calculated as a percentage of the diameter of the tablet was measured using a 100 mm round-flat probe at 0.1 mm / s at a rate of 0.1 mm / s, and the result is shown in FIG. .
  • the porous gastric retention layer has a much lower resistance to compressive force after swelling compared to the nonporous gastric retention layer.
  • the ratio of the polymer may decrease the strength and the hardness of the tablet itself. You can check it.
  • the hardness of the porous gastric retention layer prepared in Example 1 was confirmed using a hardness tester (Tablet Tester 6D, Dr. Schleuniger, Thun, Switzerland).
  • the tablet when the camphor is used as a sublimable material, the tablet is manufactured up to 40% w / w. However, when menthol is used as the sublimable material, the tablet is manufactured up to 20% w / w and from 30% w / w. The cracking phenomenon occurs, the hardness can be confirmed that the effect is very low. Therefore, in order to manufacture a robust tablet, it is preferable to manufacture 40% w / w or less for camphor and 20% w / w or less for menthol.
  • Porous bilayer tablets were prepared through two direct strokes of the gastric retention layer containing the drug layer and the sublimable material.
  • the composition is shown in Table 6. All compositions remained constant except for the ratio of HPMC, the sustained release agent of the drug release layer, and spray-dried lactose, the excipient.
  • HPMC Metal TM K4M DC2
  • spray dried lactose for direct hitting (Flowlac® 90)
  • MCC for direct hitting
  • Colloidal silicon dioxide and magnesium stearate were used as lubricants and lubricants, respectively.
  • the components, except lubricant, were weighed and mixed using a powder mixer (Turbula® T2F, WAB, Muttenz, Switzerland) for 5 minutes at a speed of 72 rpm. Lubricant was added to the resulting powder mixture and mixed for 1 minute at a speed of 72 rpm using a powder mixer.
  • Polyox TM WSR-303 PEO having a molecular weight of 7,000,000, was used as a hydrophilic swellable polymer in the gastric retentive layer containing camphor. Since the initial particle size of the camper is large, it was used by grinding with a conical mill (Comil U3, Quadro, Waterloo, Canada). The screen size was 0.04 inches or 1.016 mm in hole diameter and the impeller speed was 4,500 rpm. The ground camper was mixed with 2.5% w / w of lubricant (Aerosil TM 200) to prevent aggregation using a powder mixer.
  • the powder mixer was mixed with the hydrophilic swellable polymer and lubricant for 5 minutes using a powder mixer at a speed of 72 rpm. Lubricant was added to the resulting powder mixture and the powder mixer was mixed for 1 minute at a speed of 72 rpm.
  • the powder mixture was compressed into rectangular tablets using a single hydraulic tablet press (NP-RD10, Natoli Engineering Company, Inc., Saint Charles, MO, USA).
  • the first layer, or gastric retention layer compressed the gastric retention layer with a compressive force of 0.1 ton.
  • the second layer, or drug layer was then bonded to the first layer by filling and compressing with a compression force of one ton.
  • Compressed bilayer tablets were placed in a vacuum oven (VT-6130M, Heraeus Instruments, Monroeville, Pa., USA) and sublimed under vacuum at 60 ° C. for 12 hours. The weight of the tablet before and after vacuum drying was measured to confirm sublimation of the sublimable material.
  • the dissolution test of the bilayer sustained-release tablet prepared in Example 4 was confirmed by the USP elution 2 method in three repetitions, the eluate was used 900 mL 0.1M acetate buffer (pH 4.0), the temperature is 37 ⁇ 0.5 °C, paddle The speed was 50 rpm. 3 mL of sample was taken at a constant time, filtered through a 0.2 ⁇ m nylon syringe filter (Whatman TM, GE Healthcare UK Ltd., Buckinghamshire, UK) and eluted using a validated HPLC assay.
  • Tablets containing 0, 100, 200, camphor were prepared and the internal structure was analyzed by microcomputer tomography (Inveon TM, Siemens medical solutions, Knoxville, TN, USA). The sample was rotated 360 ° and the operating conditions were a voltage of 60 kV, a current of 400 ⁇ A and an exposure time of 400 ms. Sectional and 3D images were obtained using the Cobra EXXIM software package (Exxim Computing Corp., San Francisco, CA, USA).
  • the porosity of the formulation is determined according to the ratio of the camphor when viewed through the 3D drawing and the cross section, and the pores can be expected to be uniformly distributed throughout the formulation to show a constant swelling ability. .
  • the porous gastric retentive layer will float on the drug release layer on the eluate and the drug release layer will continue to release the drug while continuously contacting the eluate.
  • the test was carried out using 12 beagle dogs (6 control groups and 6 experimental groups) weighing about 10 kg. The animals were fasted overnight before drug administration and 180 mL of liquid enteric feed (total 270 kcal, 81 kcal fat, CareWell 1.5 Plus, Korea Enteral Foods, Korea Enterals Foods) 30 minutes after the administration of a bilayer porous gastric suppository (G5 of Example 4) prepared with radiopaque fibers. As a control, a radioactive impermeable fiber was included in the drug release layer except for the gastric retention layer of G4 in Example 4, and a 10 mm round-flat punch was compressed using a hydraulic tableting machine at a pressure of 1 ton.
  • the beagle dog ingested the bilayer porous formulation of the present invention can be confirmed that the formulation stays in the stomach for more than 12 hours, even if some exceptions of the bilayer porous formulation of the present invention At least 8 hours can be seen to show the effect of gastric retention.
  • gastric retention time is distributed between 3 hours and 8 hours, and is generally distributed between 4-5 hours, so that the bilayer porous formulation of the present invention is increased as compared to the control group. It was possible to confirm the effect of gastric retention.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

La présente invention concerne : une préparation à libération prolongée comprenant une couche de libération de médicament et une couche de rétention gastrique poreuse ; et un procédé de préparation de la préparation à libération prolongée. Plus spécifiquement, la couche de libération de médicament comprend un médicament et un agent retardateur de libération, et la couche de rétention gastrique a une structure poreuse et comprend un polymère gonflable ou un polymère non gonflable. Étant donné que la préparation à libération prolongée flotte, immédiatement lorsqu'elle est ingérée, grâce à la flottabilité due à la formation de pores dans la couche de rétention gastrique, la couche de rétention gastrique peut toujours être située au niveau d'une partie supérieure dans l'estomac, de sorte que la couche de libération de médicament ne soit pas exposée à la partie supérieure d'un fluide corporel et, par conséquent, la présente invention peut maintenir une libération de médicament pendant une longue durée. De plus, la présente invention comprend un polymère gonflable ou un polymère non gonflable dans la couche de rétention gastrique de sorte que la préparation présente une excellente résistance.
PCT/KR2018/004209 2017-04-10 2018-04-10 Préparation à libération prolongée comprenant une couche de rétention gastrique poreuse, et son procédé de préparation WO2018190621A1 (fr)

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KR20170045983 2017-04-10
KR10-2017-0045983 2017-04-10
KR1020180040904A KR102046248B1 (ko) 2017-04-10 2018-04-09 다공성 위체류층을 포함하는 서방성 제제 및 이의 제조방법
KR10-2018-0040904 2018-04-09

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CN115666532A (zh) * 2020-05-28 2023-01-31 研成精密化学株式会社 含有利马前列素的缓释制剂
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